Process for the manufacture of a thiophan derivative



Patented Nov. 16, 1948 mooess ironjmnc MA UFAcmLmE, ioF-A EHIOPHAN-rDERIMATIYE ort -scanner, "zlean-"Pierre' Bourqiiin, and Andr "-Griissner; Basel, 'Switzerlandass'ignors to Hoffunann- La'Ro'che Ina, Nutley, N. J., a corpora- 'tion of NewlJer-sey Ni -Drawing. Application January .29, 1414s, Sleifial No. 644186. "In Switzerland February "2,

'2-zclaims. 3.1 "The present invention relates to themanufacture of a thiophan derivative.

lE'atent No. 2 ,417,326 (application *Se'r. -No. '5855570 of which the inst-ant application is a continuation-impart) embodies-a process-"for the manufact'ure o'f tl iiopl'ian derivatives related -to biotin; o' f the'f0l10wil'iggenei*a1 formu1a om-pawn s V oo pew-Guam wherein X: is an' alkyl radical ror Can cniegae'su'b- Istitutedt alkyl radical. 'I'hereby, l2-'X'-3 eoxo thiophan-i-carboxylic 'acid esters rare (employed :as starting materials which .-*are converted in several "steps .by Way "of n2-X-thiophan+3giedicarboxylic-acid-ester into the previously Pmentione'd compounds. In accordance with the ipresent -.-invention, a compoundhavingthe activity ofxbiotin is obtained :if i-2-(omega-tmethoxy buty1)- "thiophan-BA-dicarboxylic acid ester is used as starting: material. This compoundiconsists xiia mixture of rstereoisom'eres the preparation and :properties "of the material, which represents -an intermediate product in "the process :of :the .said

patent, are described in the patentspeclfication cited above.

According to application 58'5-,5'l0,-i-thiophan-rone- (-3) '-*carboxylic. acid l esters :can Zbe :used as :start- *oxyalkylor omega-halogenalkyl-radicals. The

thiophan-one-(3) -carboxylic :acid esters .(.I), which 1 carry a suitable substituent 1 in position :2,

are initially converted into thecorresponding-cyanohydrins l-(II) by means of hydrocyanic acid.

The 'same are saponified without further-Mpurification and the resulting dicarboxylic acids (III) esterified. -The 3-hydroxythioph-anee3 ,4- dicarboxylic acid esters (IV), substituted in position 2, are oils capable ofbeing distilled. Upon reacting with "halides of @phosphorus and 58111- "phur, e. githionylcchloride, they'iaretransforme'd' into the 3-chlorine esters W); .By means :of reducing agents the halogen :can "be eliminated,

whereby the thiophan-3;4-dicarboxylic acid esters (VDgsubstituted in position a are bbtained. p V This synthesisrmay be. ilIuStrated byttheA {anew- 55 edissolved -."in :500 ":pa'rts by volume :of: chloroform Compounds 5 ,2 ing reactio'ni'sc'heme, which appears in our co- --pending application 585570:

6112 011 0003 CHzCH-OOOR V VI ilnthesefo'rmulaelR stands for lower alkyl, and X'is'f'an alkyl radical, or an omega-substituted radical, and more particularly, an aliphatic omega-substituted"alkyl radical.

A'specific method for preparingthe dicarboxylic acid ester, according to our application 5852570; is givenasi follows BOLpartS by weight of finely powdered potassium "cyanide .are added to a solution of 18 parts by weight of 2-methy1-3-0X0-thiophan-4car- "box-3 11c:acid=ethyl-ester in 500 parts by volfume-ofether. While stirring and cooling well, 90*parts by volume of concentrated hydrochloric facidareadded dropwise-in the course of about 2 hours. After evaporation of the ether, 300 parts by volumeof ethyl'alcohol and 300 parts by vol umeof "concentrated hydrochloric acid are added to the remaining2methyl-3-hydroXy-3-cyano- "thiophan-"kcarboXylic=acid-ethyl-ester; saponifi- "cation lse'fiected by first slowly distilling off the alcohol and thenallowin the product to stand in a boiling water bath for another 2 hours. By r concentration in l vacuo, Z-methyl-B -hydroxy-thi ophan -3fl4-dicarboxylic acid is obtained, which 'can be =converted into the 2-methyl-3-hydroXy- -'thiophan- -3;4-'dicarboxylic-acid diethyl ester without 'further purificationby means of ethyl talcohol-iandhydrochloricacid. It boils at a pres- :isure ofi0305 mmratlOl to 102C; as analmost "coloui'lesa'vis'cous 011.

@5262 :parts i b .weight of 2-methyl-3-hydroxy- "thidfihan 4' 'carboxylic-acid-diethy1-ester are and successively treated with 80 parts by volume of pyridine and 119 parts by volume of thionyl chloride while cooling well with ice. The prodnot is first allowed to stand for 2 hours and then heated for about 40 minutes in a boiling water bath until the evolution of gas has ceased. Thereupon, the product is poured on ice, divided in a separating funnel and washed with water and dilute sodium carbonate solution until neutral reaction sets in. The 2-methyl-3-chlorothiophan-3,4-dicarboxylic-acid-diethyl-ester separated from the chloroform boils at a pressure of 0.1 mm. at 100 to 102 C.

186 parts by Weight of sodium-iodide hydrate are added to a solution of 280parts by Weight of 2-methyl-3-chloro thiophan 3,4 dicarboxylicacid-diethyl-ester in 4000 parts by volume of 80 per cent. acetic acid, and 1400 parts by weight of zinc dust introduced in small portions in the course of about 4 hours while stirring. Each time slight warming set in. After further stirring for about 12 hours, the zinc acetate is separated, the acetic acid removed by distillation and the residue distilled in vacuo after thoroughly Washing with water and sodium carbonate solution. The 2 methyl thiophan-3,4-dicarboxylic-acid-diethyl-ester boils at a pressure of 0.02

' mm. at 88 to 90 C. as a colourless oil.

The preparationof 2- (omega-methoxy-butyl) thiophan-3,e-dicarboxylic-acid diethyl ester is described in our copending application 585,570. In this synthesis, 80 parts by weight of finely pulverised potassium cyanide are added to a solution of 260 parts by weight of 2-(omega-methoxybutyl) 3-oxo-thiophan-4-carboxylic-acid-ethyl ester in 540 parts by volume of dibutyl ether and then 106 parts by volume of concentrated hydrochloric acid allowed to drop in during 8 hours while stirring and cooling with ice. The reaction mixture is left to stand overnight at 0 C. The crystallized cyanohydrin with the potassium chloride is separated from the dibutyl-ether solution by suction. The separation of the cyanohydrin from the potassium chloride is effected by dissolving the former in chloroform. The chloroform solution is dried with sodium sulphate and after filtration brought to dryness in vacuo at a bath temperature of 30 C. The 2-(omegamethoxybutyl) -3-hydroxy-3-cyano thiophan-4- carboxylic-acid-ethyl-ester, obtained in almost theoretical yield, has a melting point of 88 C. The methyl ester melts at 81.5 to 835 C.

287 parts by Weight of 2-(omega-methoxybutyl) -3-hydroxy-3-cyano thiophan-4-carboxylicacid-ethyl-ester are reacted with a. mixture of 600 parts by volume of concentrated hydrochloric acid, 300 parts by volume of water and 1100 parts by volume of ethyl alcohol and boiled under reflux for 48 hours. After evaporation in vacuo, the saponified product is converted into the 2- (omega-methoxybutyl) -3-hydroxythiophan-3,4- dicarboxylic-acid-diethyl-ester by means of ethyl alcohol and hydrogen-chloride gas. It boils at a pressure of 0.07 mm. at 145147 C. as a lightyellow, viscous oil. The dimethyl ester boils at a pressure of 0.09 mm. at 146-149 C.

334 parts by Weight of 2-(omega-methoxybutyl) -3-hydroxy thiophan-3,4-dicarboxylic-aciddiethyl-ester are dissolved in 660 parts by volume of chloroform and reacted with 154 parts by weight of absolute pyridine and 231 parts by Weight of thionyl chloride While cooling with ice. Reaction and working-up in accordance with the process as applied to the methyl-substituted compound described above yields a yellowish-brown,

'4 viscous oil, viz. 2-(omega-methoxybutyl) -3-chlo ro-thiophan-3A dicarboXylic-acid-diethyl ester, melting point 138-143 C. at 0.03 mm. The dimethyl ester boils at 134 to 137 C. under a pressure of 0.03 mm.

353 parts by weight of 2-(omega-methoxybutyl) -3-chloro-thiophan-3A-dicarboxylic acid-diethyl ester are dissolved in 5100 parts by volume of per cent. acetic acid, 230 parts by weight of potassium iodide are added, and, while stirring, 1550 parts by weight of zinc dust are introduced in small portions in the course of 4 hours at a temperature not exceeding 20-25 C. After working-up in accordance with the process as applied to the methyl-substituted compound described above, the 2-(omega-methoxybutyl) thiophan 3,4 dicarboxylic acid diethyl-ester boils as a light-yellowish oil at 148 to 150 C. under a pressure of 0.03 mm. The Z-(omega-methoxybutyl) thiophan-3,4-dicarboxylic acid dimethyl-ester boils at 141 to 143 C. under a pressure of 0.03 mm.

According to the present invention, 2-(omegamethoxybutyl) -thiophan-3,4 dicarboxylic acidester is reacted with hydrazine-hydrate. The mother-liquor, which remains behind after separation of a crystallising compound, is treated with sodium-nitrite, the acid azide thus resulting is decomposed to yield 3,4-diurethane by heating with alcohol, the solution is evaporated under reduced pressure, and from the benzene solution of the residue a fraction capable of being eluted comparatively easily is separated by chromatography. The more difficultly elutable fraction is converted into the dihydrobromide of 2-(omega-bromobutyl) -3,4-diamino-thiophan by heating with hydrobromic acid and the resulting salt reacted with phosgene. Potassium-cyanide and a saponifying agent are successively caused to act on the resulting reaction product, whereupon, after acidification, the resulting 2-(omega-carboxy butyl) -3,4-(imidazolidone 2) thiophan can be isolated in crystalline form.

The isolation of the crystalline final product can, for instance, be effected by esterifying the resulting 2 (omega carboxy butyl) 3,4-(imidazolidone-2') -thiophan, crystallising the ester from the eluate after chromatographic purification and, for the purpose of obtaining the crystalline carboxylic acid, a saponifying agent is caused to act thereon.

The compound thus obtained has the following formula:

The sterically uniform, racemic compound crystallises in colorless needles melting at 233- 235 C.; it is not soluble in ether, diflicultly soluble in cold water and more easily soluble in ethyl and methyl alcohol. When biologically tested, the product shows the action of biotin with regard to the growth of Saccharomyces cereviszae and Streptococcus Zactis.

Example 318.5 parts by Weight of 2-(omega-methoxybutyl)-thiophan-3,4-dicarboxylic-acid diethylester are dissolved in 1650 parts by volume of methanol and boiled under reflux with 200 parts by weight of hydrazine-hydrate for '72 hours. On cooling, a dihydrazide of melting point 204- 205.C. separates. Thev mother-liquor is evaporated in vacuo and the oily product thus obtained is used for further proceedings.

290 parts by weight of oily Z-(omega-methoxybutyl)-thiophan-3,4-dicarboxylic acid dihydrazide are dissolved in 835 parts by volume of 3 n-hydrochloric acid, covered with a layer of 8000 parts by volume of ether and treated with a solution of 138 parts by weight of sodiumnitrite in 1000 parts of water added dropwise, while stirring and cooling with ice. The ethersolution containing the azide is evaporated in vacuo at a bath-temperature of 25 0., the residue taken up in 7000 parts by volume of absolute alcohol and transformed into the urethane by heating to 75 C. The alcoholic solution is completely evaporated in vacuo; the residue contains the urethane in the form of a viscous oil. The same is dissolved in 5000 parts by volume of benzene, whereupon the solution is adsorbedonto an aluminum-oXide-column. After Washing With benzene, elution is effected with chloroform; the eluate is brought to dryness under reduced pressure.

348 parts by weight of 2-(omega-methoxybutyl)-3,4-diurethano-thiophan are heated to 100-105" C. with 4000 parts by volume of 48 per cent hydrobromic acid until the evolution of carbon-dioxide has come to an end. After evaporation of the hydrobromic acid in vacuo, the dihydrobromide remains behind as a hygroscopic mass.

415 parts by weight of 2-(omega-bromobutyl) 3,4-diamino-thiophan-dihydrobromide are dissolved in 2000 parts by volume of an aqueous nsolution of caustic soda and, while stirring and cooling with ice, treated with 99 parts by weight of phosgene (in form of a 20 per cent solution in toluene) and 2000 parts by volume of an aqueous n-solution of caustic soda, the lye and the phosgene-solution being added simultaneously in such a manner that the pH of the solution is 7 to 8. The reaction product is brought to dryness in vacuo, extracted with alcohol and the alcohol solution evaporated in vacuo. The crude product thus obtained is immediately worked up further.

279 parts by weight of 3,4-(imidazolidone-2') 2-(omega-bromobutyl) -thiophan in 2000 parts'by volume of alcohol are boiled under reflux for 24 hours with 65 parts by weight of potassiumcyanide. parts by weight of potassium-hydroxide in 2000 parts of water are added and saponifie'd for 2 hours at 90 C. The alkaline solution is filtered, set acid to Congo with hydrochloric acid and concentrated in vacuo.

The residue is dissolved in methyl alcohol, esterified with diam-methane and evaporated in vacuo. The remaining oil is dissolved in chloroform, whereupon the solution is adsorbed onto an After evaporation of the alcohol, 112

aluminum-oxide-column. The chromatogram is first washed with chloroform, whereupon the ester is eluted with acetone. Upon concentration of the acetone-eluate, the dl-3,4-(imidazolidone- 2) 2-(omega carbomethoxy butyl)-thiophan crystallises in colorless needles which, after recrystallisation from acetic ester or methylalcohol-ether mixture, show a melting point of 131-132 C. For saponification purposes, the methyl-ester is heated for a short while with a dilute aqueous solution of caustic soda. After adding hydrochloric acid to the solution until it reacts acid to Congo, the dl-3,4-(imidazolidone- 2')-2-(omega carbohydroxy butyl) -thiophan crystallises out. After recrystallisation from water, the crystal needles show a melting point of 233-235 C.

Subject matter disclosed herein but not claimed in this application is claimed in applicants copending application Serial No. 744,774, filed April 29,1947.

We claim:

1. Process for the manufacture of a thiophan derivative, comprising reactin 2-(omega-methoxy-butyD-thiophan 3,4 dicarboxylic acidester with hydrazine-hydrate, treating the mother-liquor remaining after separation of crystalline hydrazide with sodium-nitrite, decomposing the resulting acid azide by heating with alcohol to yield the 3,4-diurethane, evaporating the solution under reduced pressure, dissolving the residue in benzene, passing the solution through a column of aluminum oxide, washing with benzene, eluting with chloroform, evaporating to dryness and converting the residue into the dihydrobromide of 2-(omega-bromobutyl) -3,4-diamino-thiophan by heating with hydrobromic acid, reacting the resulting salt with phosgene, successively causing potassiumcyanide and a saponifying agent to act on the resulting reaction product and isolating the resulting 2- (omega-carboxy-butyl) -3,4- (imidazolidone-2)-thiophan in crystalline form after acidification.

2. Process in accordance with claim 1, comprising esterifying the resulting 2-(omegacarboxy butyl) 3,4 (imidazolidone-2') -thiophan, dissolving the ester in chloroform, passing the solution through a column of aluminum oxide, washing with chloroform, eluting with acetone, crystallising the ester from the eluate and causing a saponifying agent to act thereon for the purpose of obtaining the crystalline carboxylic acid.

OTTO SCHNIDER. JEAN-PIERRE BOURQUIN. ANDRE GRiissNER.

No references cited. 

